Mitochondrial respiratory dysfunction caused by a heteroplasmic mitochondrial DNA mutation blocks cellular reprogramming.
Mitochondrial respiratory dysfunction caused by a heteroplasmic mitochondrial DNA mutation blocks cellular reprogramming.
复制标题
由异质线粒体 DNA 突变引起的线粒体呼吸功能障碍会阻碍细胞重编程。
DOI：
10.1093/hmg/ddv201
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发表时间：
2015
影响因子：
3.5
通讯作者：
Goto Y
中科院分区：
文献类型：
--
作者：
Yokota M;Hatakeyama H;Okabe S;Ono Y;Goto Y
只有当突变的线粒体DNA（mtDNA）比例超过内在致病阈值时，线粒体tRNA基因的致病性突变引起的线粒体功能障碍才会出现;然而，关于突变的mtDNA的实际比例知之甚少，这些比例可以影响特定的细胞谱系决定过程。本文主要研究MT-TL 1基因m.3243A>G异质性导致的线粒体呼吸功能障碍对细胞重编程的影响。我们发现，诱导多能干细胞（iPSC）的产生仅受到高比例突变mtDNA（≥90% m.3243A>G）的显著抑制，并且这些比例与诱导线粒体呼吸功能障碍的程度密切相关。尽管如此，所有建立的iPSC，甚至那些携带100% m.3243A>G的iPSC，都表现出胚胎干细胞样的多能状态。因此，我们的研究结果清楚地表明，突变mtDNA引发的线粒体生理完整性的丧失构成了细胞复壮的障碍，但不影响多能状态的维持。
Mitochondrial dysfunction caused by pathogenic mutations in mitochondrial tRNA genes emerges only when mutant mitochondrial DNA (mtDNA) proportions exceed intrinsic pathogenic thresholds; however, little is known about the actual proportions of mutant mtDNA that can affect particular cellular lineage-determining processes. Here, we mainly focused on the effects of mitochondrial respiratory dysfunction caused by m.3243A>G heteroplasmy inMT-TL1gene on cellular reprogramming. We found that generation of induced pluripotent stem cells (iPSCs) was drastically depressed only by high proportions of mutant mtDNA (≥90% m.3243A>G), and these proportions were strongly associated with the degree of induced mitochondrial respiratory dysfunction. Nevertheless, all established iPSCs, even those carrying ∼100% m.3243A>G, exhibited an embryonic stem cell-like pluripotent state. Therefore, our findings clearly demonstrate that loss of physiological integrity in mitochondria triggered by mutant mtDNA constitute a roadblock to cellular rejuvenation, but do not affect the maintenance of the pluripotent state.